Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II.
Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II.
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DOI：
10.1172/jci16326
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发表时间：
2003-03
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通讯作者：
Weizhong Zhu;Shi-Qiang Wang;K. Chakir;Dongmei Yang;Tong Zhang;J. Brown;E. Devic;B. Kobilka;
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作者：
Weizhong Zhu;Shi-Qiang Wang;K. Chakir;Dongmei Yang;Tong Zhang;J. Brown;E. Devic;B. Kobilka;
β（1）-肾上腺素能受体（β（1）AR）刺激激活经典的cAMP/蛋白激酶A（PKA）途径以调节重要的细胞过程，从基因表达的改变到代谢、肌肉收缩和细胞凋亡的控制。我们发现持续的β 1 AR刺激通过激活Ca（2+）/钙调蛋白激酶II（CaMKII）促进心肌细胞凋亡，而不依赖于PKA信号。β（1）AR诱导的细胞凋亡对特异性肽抑制剂PKI 14 -22或无活性cAMP类似物Rp-8-CPT-cAMPS抑制PKA具有抗性。相反，β（1）AR促凋亡作用与细胞内Ca（2+）和CaMKII活性的非PKA依赖性增加有关。阻断L-型Ca（2+）通道、缓冲细胞内Ca（2+）或抑制CaMKII活性可完全保护心肌细胞免受β（1）AR诱导的凋亡，并且过表达心脏CaMKII亚型CaMKII-deltaC可显著增强β（1）AR的凋亡效应。这些发现表明，CaMKII构成了一种新的PKA-独立的β（1）AR刺激心肌细胞凋亡的联系，已被牵连在慢性心力衰竭的整个过程。
beta(1)-adrenergic receptor (beta(1)AR) stimulation activates the classic cAMP/protein kinase A (PKA) pathway to regulate vital cellular processes from the change of gene expression to the control of metabolism, muscle contraction, and cell apoptosis. Here we show that sustained beta(1)AR stimulation promotes cardiac myocyte apoptosis by activation of Ca(2+)/calmodulin kinase II (CaMKII), independently of PKA signaling. beta(1)AR-induced apoptosis is resistant to inhibition of PKA by a specific peptide inhibitor, PKI14-22, or an inactive cAMP analogue, Rp-8-CPT-cAMPS. In contrast, the beta(1)AR proapoptotic effect is associated with non-PKA-dependent increases in intracellular Ca(2+) and CaMKII activity. Blocking the L-type Ca(2+) channel, buffering intracellular Ca(2+), or inhibiting CaMKII activity fully protects cardiac myocytes against beta(1)AR-induced apoptosis, and overexpressing a cardiac CaMKII isoform, CaMKII-deltaC, markedly exaggerates the beta(1)AR apoptotic effect. These findings indicate that CaMKII constitutes a novel PKA-independent linkage of beta(1)AR stimulation to cardiomyocyte apoptosis that has been implicated in the overall process of chronic heart failure.